Comptonellins A–H, Highly Potent Antiviral Ternatin-type Cyclopeptides from Comptonella drupacea

An antiviral screening of plant extracts from Rutaceae and Annonaceae families led to the isolation of a series of new cycloheptapeptides, comptonellins A-H (1-8), along with the known ternatin (9). These compounds were isolated from the ethyl acetate bark extract of Comptonella drupacea (Labill.) Guillaumin, an endemic Rutaceae species of New Caledonia. Following targeted isolation guided by multi-informative molecular networks, the structures of compounds 1-9 were elucidated through a comprehensive analysis of spectroscopic data. This revealed novel molecules featuring previously unreported and noncanonical amino acids. The absolute configuration of stereocenters was partially determined by advanced Marfey's method. Biological evaluation against Zika virus demonstrated the potent antiviral properties of comptonellin A and comptonellins C-G, with IC50 values ranging from 7 to 240 nM. Further investigations revealed that comptonellin A displayed broad-spectrum antiviral activity, inhibiting Dengue virus, Ross River virus, and SARS-CoV-2. These findings highlight comptonellins as promising antiviral scaffolds, supporting further investigation into their therapeutic potential against emerging viral infections.